N-carbamate protected α-amidoalkyl-p-tolylsulfones: Convenient substrates in the aza-Morita-Baylis-Hillman reaction

Article abstract of DOI:10.1021/jo801616d

(Chemical Equation Presented) An efficient and practical one-pot approach to aza-Morita-Baylis-Hillman adducts has been developed. The reaction occurs between N-Boc or N-Cbz imines, generated in situ from stable and easy to handle N-Boc or N-Cbz protected

Full text of DOI:10.1021/jo801616d

SCHEME 1. Aza-MBH Reaction
N-Carbamate Protected
r-Amidoalkyl-p-tolylsulfones: Convenient
Substrates in the aza-Morita-Baylis-Hillman
Reaction
Anna Gajda and Tadeusz Gajda*
Institute of Organic Chemistry, Technical UniVersity of Lodz,
˙
Zeromskiego St. 116, 90-924 Lodz, Poland
tmgajda@p.lodz.pl
tected ones, are seldom used in aza-MBH reactions,3t,u,7 despite
their high reactivity and easy removal of the protecting group
(Scheme 1), because of their substantial hydrolytic lability,
especially for those derived from aliphatic aldehydes. Therefore,
certain precautions have to be taken in their preparation,
handling, and storage.
ReceiVed July 22, 2008
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Commun. 2006, 36, 2491. (s) Matsui, K.; Takizawa, S.; Sasai, H. Synlett 2006,
761. (t) Shi, Y.-L.; Shi, M. Tetrahedron 2006, 62, 461. (u) Clary, K. N.; Back,
T. G. Synlett 2007, 2995. (w) Sorbetti, J. M.; Clary, K. N.; Rankic, D. A.; Wulff,
J. E.; Parvez, M.; Back, T. G. J. Org. Chem. 2007, 72, 3326.
An efficient and practical one-pot approach to aza-
Morita-Baylis-Hillman adducts has been developed. The
reaction occurs between N-Boc or N-Cbz imines, generated
in situ from stable and easy to handle N-Boc or N-Cbz
protected R-amidoalkyl-p-tolylsulfones, and electron-defi-
cient alkenes in the presence of DABCO. The presented
procedure eliminates the use of the relatively unstable
N-carbamate imines prior to the coupling reaction. The
reaction is limited to R-amidosulfones derived from aromatic
and heteroaromatic aldehydes.
The aza-Morita-Baylis-Hillman (aza-MBH) reaction1 oc-
curring between activated imines 1 and R,ꢀ-unsaturated carbonyl
compounds, in the presence of tertiary amine or tertiary
phosphine, provides straightforward and atom-economic method
for the synthesis of highly functionalized N-protected R-meth-
ylene-ꢀ-aminocarbonyl compounds 2, potential building blocks
often used for the preparation of biologically important
compounds1a,b,d,g,2 (Scheme 1). Recently, the asymmetric ver-
sion of the aza-MBH reaction is also the subject of intensive
and very promising studies.1h,e,f,3 N-Sulfonylated imines, derived
from aryl and heteroaryl aldehydes or cinnamaldehyde, are the
commonly used electrophiles in aza-MBH reactions.3a-n,4-6
Aromatic N-carbamate activated imines, especially Boc pro-
(5) For the use of N-phosphorylated and N-phosphinylated imines and their
thio analogues, see: (a) Zwierzak, A.; Napieraj, A. Phosphorus, Sulfur and Silicon
1999, 144-146, 93. (b) Shi, M.; Zhao, G.-L. Tetrahedron Lett. 2002, 43, 4499.
(c) Xu, X.; Wang, C.; Zhou, Z.; Tang, X.; He, Z.; Tang, C. Eur. J. Org. Chem.
2007, 4487. (d) See ref 3p.
(6) For the use of N-(aryl)imines, see: (a) Liu, X.; Chai, Z.; Zhao, G.; Zhu,
S. J. Fluorine Chem. 2005, 126, 1215. (b) Gao, J.; Ma, G.-N.; Li, Q.-J.; Shi, M.
Tetrahedron Lett. 2006, 47, 7685. (c) See ref 3r,s.
(7) (a) Yamamoto, K.; Takagi, M.; Tsuji, J. Bull. Chem. Soc. Jpn. 1988, 61,
319. (b) Xu, Z.; Lu, X. J. Org. Chem. 1998, 63, 5031. (c) Sergeeva, N. N.;
Golubev, A. S.; Hennig, L.; Findeisen, M.; Paetzold, E.; Oehme, G.; Burger, K.
J. Fluorine Chem. 2001, 111, 41.
(1) For reviews on the Morita-Baylis-Hillman reaction and its aza-
counterpart, see: (a) Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996,
52, 8001. (b) Ciganek, E. Org. React. 1997, 51, 201. (c) Langer, P. Angew.
Chem., Int. Ed. 2000, 39, 3049. (d) Basavaiah, D.; Rao, A. J.; Satyanarayana,
T. Chem. ReV. 2003, 103, 811. (e) Krishna, P. R.; Sharma, G. V. M. Mini-ReV.
Org. Chem. 2006, 3, 137. (f) Masson, G.; Housseman, C.; Zhu, J. Angew. Chem.,
Int. Ed. 2007, 46, 4614. (g) Shi, Y.-L.; Shi, M. Eur. J. Org. Chem. 2007, 2905.
(h) Basavaiah, D.; Venkateswara, R.; Reddy, R. J. Chem. Soc. ReV. 2007, 36,
1581.
(2) Singh, V.; Batra, S. Tetrahedron 2008, 64, 4511.
10.1021/jo801616d CCC: $40.75
Published on Web 09/27/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 8643–8646 8643

TABLE 1. Optimization of the aza-MBH Reactiona
SCHEME 2. Three-Component aza-MBH Reaction
DABCO
(equiv)
methyl acrylate
(equiv)
time
(d)
entry
solvent
Yield
1
2
3
4
0.2
1.2
2.0
1.2
25
25
25
2
acrylate
acrylate
acrylate
THF
9
2
2
8
65
68
69
b
The instability of imines could be partly circumvented in a
one-pot three-component aza-MBH reaction3w,8 in which alde-
hydes and amides 3 reacted with electron-deficient alkenes in
the presence of tertiary amines such as DABCO, 3-hydroxyqui-
nuclidine, or triphenylphosphine (Ph3P) (Scheme 2).
In several protocols high yields were additionally ensured
by using catalytic amounts of Lewis acids such as La(OTf)3,
Ti(OPri)4, or TiCl4 and molecular sieves as additives.8c-g,j-l
Generally, the transformations mentioned above were limited
to aromatic and heteroaromatic aldehydes. In some cases the
concomitant formation of the corresponding hydroxy-MBH
adducts was additionally observed.8c,g Arylsulfonamides, 2-tri-
methylsilylethylsulfonamide (SES-NH2), and diphenylphosphi-
namide were very often used as a source of amine-protecting
group. For the synthesis of N-sulfonylated aza-MBH adducts
derived from aliphatic aldehydes, microwave-assisted three-
component aza-MBH reaction was especially useful.8i
The isolated examples of the N-Boc and N-Cbz protected aza-
MBH adducts,9 formed in Ph3P-catalyzed reaction of tert-butyl
or benzyl carbamate, benzaldehyde, and MVK or methyl
acrylate as Michael acceptors, were also reported.8a Neverthe-
less, Balan and Adolfsson8c found that tert-butyl and benzyl
carbamate, previously reported to yield aza-MBH adducts8a gave
no desired products in the three-component aza-MBH reactions
either by using Lewis acid/base catalyzed three-component
protocol or when Ph3P was applied as catalyst.10
a Reactions were run with 4a (5.0 mmol) and DABCO (0.2-2 equiv)
in methyl acrylate (2-25 equiv) at room temperature. The progress of
the reaction was monitored by TLC (hexanes/AcOEt 2:1 v/v) and 1H
NMR. Disappearance of the starting 4a and the intermediate N-Boc
imine 6a was traced. b A large amount of 6a was still present in the
reaction mixture after 8 d at room temperature.
crystalline, and easy to handle equivalents of N-Boc and N-Cbz
imines. Therefore nucleophilic additions to N-carbamate imines
generated in situ from the R-amidosulfones mentioned above
by base-induced elimination have been recently the subject of
extensive studies.9i,13
For this reason, we thought it would be of interest to develop
a new protocol, which for the first time would give the
opportunity to use the N-carbamate protected R-amidoalkyl-p-
tolylsulfones in the aza-MBH reactions. Herein we report our
efforts to achieve this goal.
At first, we examined the model reaction of N-Boc R-ami-
doalkyl-p-tolylsulfone 4a with methyl acrylate using DABCO
simultaneously as a base and catalyst. The results are sum-
marized in Table 1.
Initially, the reaction was performed under the standard MBH
conditions using 20 mol % DABCO and methyl acrylate as a
solvent. However, the reasonable yield of the desired aza-adduct
5a was achieved only after 9 d at room temperature (Table 1,
entry 1). In turn, increasing DABCO amount to 1.2 equiv with
respect to 4a resulted in the formation of 5a in 68% yield within
2 d at room temperature (Table 1, entry 2). Further increase of
DABCO amount to 2.0 equiv had no influence on either the
reaction rate or its yield (Table 1, entry 3). Finally, reducing
the amount of methyl acrylate to 2 equiv and using THF as
solvent caused a dramatic decrease of the reaction rate. After
8 d at room temperature the conversion was still very low, as
confirmed by 1H NMR analysis of the reaction mixture (Table
1, entry 4).
It is well documented that N-Boc and N-Cbz protected
R-amidoalkyl-p-tolylsulfones11,12 4 can be considered as stable,
(8) (a) Bertenshaw, S.; Kahn, M. Tetrahedron Lett. 1989, 30, 2731. (b)
Richter, H.; Jung, G. Tetrahedron Lett. 1998, 39, 2729. (c) Balan, D.; Adolfsson,
H. J. Org. Chem. 2001, 66, 6498. (d) Balan, D.; Adolfsson, H. J. Org. Chem.
2002, 67, 2329. (e) Shi, M.; Zhao, G.-L. Tetrahedron Lett. 2002, 43, 9171. (f)
Balan, D.; Adolfsson, H. Tetrahedron Lett. 2004, 45, 3089. (g) Declerck, V.;
Ribie`re, P.; Martinez, J.; Lamaty, F. J. Org. Chem. 2004, 69, 8372. (h) Ribie`re,
P.; Enjalbal, C.; Aubagnac, J.-L.; Yadav-Bhatnagar, N.; Martinez, J.; Lamaty,
F. J. Comb. Chem. 2004, 6, 464. (i) Ribie`re, P.; Yadav-Bhatnagar, N.; Martinez,
J.; Lamaty, F. QSAR Comb. Sci. 2004, 23, 911. (j) Vasudevan, A.; Tseng, P.-S.;
Djuric, S. W. Tetrahedron Lett. 2006, 47, 8591. (k) Declerck, V.; Allouchi, H.;
Martinez, J.; Lamaty, F. J. Org. Chem. 2007, 72, 1518. For leading TiCl4-
mediated Baylis-Hillman reactions, see: (l) Li, G.; Wei, H.-X.; Gao, J. J.; Caputo,
T. D. Tetrahedron Lett. 2000, 41, 1.
(9) For an alternative synthesis of N-Boc and N-Cbz protected aza-MBH-
type adducts, see: (a) Ciclosi, M.; Fava, C.; Galeazzi, R.; Orena, M.; Sepulveda-
Arques, J. Tetrahedron Lett. 2002, 43, 2199. (b) Zhang, Y.; Liu, Y.-K.; Kang,
T.-R.; Hu, Z.-K.; Chen, Y.-C. J. Am. Chem. Soc. 2008, 130, 2456. (c) Huck, J.;
Duru, C.; Roumestant, M. L.; Martinez, J. Synthesis 2003, 2165. (d) Wa¸sek, T.;
Olczak, J.; Janecki, T. Synlett 2006, 1507. (e) Sergeeva, N. N.; Golubev, A. S.;
Hennig, L.; Burger, K. Synthesis 2003, 915. (f) Brown, J. M.; James, A. P.;
Prior, L. M. Tetrahedron Lett. 1987, 28, 2179. (g) Seebach, D.; Jacobi, A.;
Rueping, M.; Gademann, K.; Ernst, M.; Jaun, B. HelV. Chim. Acta 2000, 83,
2115. (h) Bierbaum, D. J.; Seebach, D. Aust. J. Chem. 2004, 57, 859. (i) Gajda,
A.; Gajda, T. Tetrahedron 2008, 64, 1233.
(12) For the synthesis of N-Boc and N-Cbz protected R-amidosulfones, see:
(a) Engeberts, J. B. F. N.; Strating, J.Rec. TraV. Chim. Pays-Bas 1964, 83, 733.
(b) Pearson, W. H.; Lindbeck, A. C.; Kampf, J. W. J. Am. Chem. Soc. 1993,
115, 2623. (c) Kanazawa, A. M.; Denis, J.-N.; Greene, A. E. J. Org. Chem.
1994, 59, 1238. (d) Mecozzi, T.; Petrini, M. J. Org. Chem. 1999, 64, 8970. (e)
Murry, J. A.; Frantz, D. E.; Soheili, A.; Tillyer, R.; Grabowski, E. J.; Reider, P.
J. Am. Chem. Soc. 2001, 123, 9696. (f) Bernacka, E.; Klepacz, A.; Zwierzak, A.
Tetrahedron Lett. 2001, 42, 5093. (g) Klepacz, A.; Zwierzak, A. Tetrahedron
Lett. 2002, 43, 1079.
(13) For selected recent applications of R-amidosulfones, see: (a) Nejman,
M.; Sliwin´ska, A.; Zwierzak, A. Tetrahedron 2005, 61, 8536. (b) Fini, F.;
´
Sgarzani, V.; Pettersen, D.; Herrera, R. P.; Bernardi, L.; Ricci, A. Angew. Chem.,
Int. Ed. 2005, 44, 7975. (c) Fini, F.; Bernardi, L.; Herrera, R. P.; Pettersen, D.;
Ricci, A.; Sgarzani, V. AdV. Synth. Catal. 2006, 348, 2043. (d) Lombardo, M.;
Mosconi, E.; Pasi, F.; Petrini, M.; Trombini, C. J. Org. Chem. 2007, 72, 1834.
(e) Song, J.; Shih, H.-W.; Deng, L. Org. Lett. 2007, 9, 603. (f) Niess, B.;
Jørgensen, K. A. Chem. Commun. 2007, 1620. (g) Nakagawa, H.; Rech, J. C.;
Sindelar, R. W.; Ellman, J. A. Org. Lett. 2007, 9, 5155. (h) Marianacci, O.;
Micheletti, G.; Bernardi, L.; Fini, F.; Fochi, M.; Pettersen, D.; Sgarzani, V.;
Ricci, A. Chem. Eur. J. 2007, 13, 8338.
(10) In our hands, attempted repetition of a three-component procedure
elaborated by Bartenshaw and Kahn8a using tert-butyl or benzylcarbamate,
benzaldehyde, methyl acrylate, and Ph3P (20 mol %) as catalyst, resulted in the
formation of the desired N-Boc or N-Cbz aza-adducts in less than 7% yield after
2 d at 40 °C in 2-propanol, as confirmed by 1H NMR analysis of the crude
reaction mixture.
(11) For reviews, see: (a) Petrini, M. Chem. ReV. 2005, 105, 3949. (b) Petrini,
M.; Torregiani, E. Synthesis 2007, 159.
8644 J. Org. Chem. Vol. 73, No. 21, 2008

TABLE 2. Formation of N-Boc and N-Cbz Protected aza-MBH
affording the desired products 5m-o in 63-75% yield within
2 d at room temperature.
Adducts 5 and 9a
To widen the scope of this new protocol, we examined
also the N-Cbz protected R-amidoalkyl-p-tolylsulfone 8a (Ar
) Ph) as starting material. It was found that the substitution
of N-Boc R-amidosulfones 4 by N-Cbz protected R-ami-
dosulfone 8a afforded the analogues 9a and 9b in 70% and
57% yields, respectively. The longer reaction time required
for the conversion of N-Cbz R-amidosulfone 8a stemmed
from its poor solubility in acrylonitrile and ethyl acrylate.
Unfortunately, the attempted use of our procedure for
N-Boc or N-Cbz protected R-amidoalkyl-p-tolylsulfones (4
or 8) derived from aliphatic aldehydes did not provide any
aza-MBH adducts. The lack of the desired products in these
cases stems probably from the fast spontaneous tautomer-
ization of the intermediate alkyl N-carbamate imines,15
formed from parent R-amidosulfones, into enecarbamates that
are not reactive under these conditions.16
In conclusion, we have demonstrated that the procedure
described here provides a new and operationally simple one-
pot access to structurally diverse aza-Morita-Baylis-Hillman
adducts from easily available and stable N-Boc and N-Cbz
protected R-amidoalkyl-p-tolylsulfones. Our protocol elimi-
nates the preformation and sometimes tedious isolation of
the unstable N-carbamate imines prior to the coupling reaction
with Michael acceptors. The aza-MBH adducts with easily
removable amine protecting group (Boc and Cbz) have been
obtained in good yields. The method has been evaluated for
a range of N-carbamate protected R-amidosulfones derived
from heteroaromatic and aromatic aldehydes, including
electron-poor and -rich as well as ortho-substituted derivatives.
compd
R
PG
EWG
time (d)
yieldb
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
9a
9b
Ph
Boc
CO2Me
2
5
2
5
2
6
5
8
4
6
2
6
2
68
76
58
72
65
71
51
76
79
66
67
64
75
66
63
70
57
4-MeOC6H4
4-BrC6H4
2-MeOC6H4
2-ClC6H4
2-furyl
3-py
1-naphthyl
Ph
4-MeOC6H4
4-BrC6H4
2-furyl
Boc
Boc
CO2Et
CN
Ph
4-MeOC6H4
4-BrC6H4
Ph
2
2
Cbz
Cbz
CO2Et
CN
7c
5c
Ph
a Reactions were run with 4 or 8 (5.0 mmol) and DABCO (1.2 equiv)
in methyl or ethyl acrylate or acrylonitrile (25 equiv) at room
temperature. b Yields of pure isolated compounds 5a-o and 9a,b, after
flash chromatography. c Prolonged reaction time resulted from the partly
heterogenic nature of the reaction mixture.
In all of the reactions mentioned above, the aza-adduct 5a
was accompanied by the formation of methyl 3-(toluene-4-
sulfonyl)-propionate14 (7a). Nevertheless, 5a could be easily
separated from the byproduct 7a by flash chromatography. The
presence of 7a in the reaction mixture could be rationalized by
the Michael-type addition of p-toluenesulfinate, released from
the R-amidosulfone 4a during the formation of the imine 6a, to
methyl acrylate.
Finally, we investigated the reactions of a series of N-Boc
protected aromatic R-amidosulfones with selected Michael-type
acceptors under the optimized protocol using 1.2 equiv of
DABCO as a base. Methyl and ethyl acrylate and acrylonitrile
were employed as Michael acceptors and as solvents concurrently.
The reaction was general, and a number of diverse aryl and
heteroaryl substituted aza-MBH adducts 5a-o were obtained
in good yields. The results are summarized in the Table 2. The
structures of products were unequivocally confirmed by NMR,
elemental analyses, and mass spectra.
The results in Table 2 show that methyl and ethyl acrylates
afford the corresponding aza-adducts 5a-l in comparable yields
(51-79%) after flash chromatography. While the presence of
an electron-withdrawing bromine atom in the para position of
the benzene ring of 4c and 4k reduced the reaction time to 2 d,
the N-Boc protected R-amidosulfones 4b,j,f,l,g,h, derived from
4-methoxybenzaldehyde, 2-furaldehyde, pyridine-3-carbalde-
hyde, or 1-naphthaldehyde required longer reactions time for
completion. Moreover, the reaction tolerates also sterically
hindered ortho-substituted R-amidosulfones 4d and 4e, giving
the appropriate o-methoxy and o-chloro substituted adducts 5d
and 5e in 72% and 65% yield, respectively. Unlike acrylates,
acrylonitrile reacted faster under the optimized conditions
Experimental Section
General Procedure. A mixture of R-amidosulfones 4 or 8 (5.0
mmol), Michael acceptor (methyl acrylate, ethyl acrylate or
acrylonitrile) (25 equiv), and DABCO (6.0 mmol, 0.67 g, 1.2
equiv) was stirred for 2-8 d at room temperature until the
1
substrates disappeared, as checked by TLC and H NMR. Then
the excess of the Michael acceptor was removed under reduced
pressure, and diethyl ether (40 mL) was added to the residue.
The crystalline methyl or ethyl 3-(toluene-4-sulfonyl)-propi-
onate14 or 3-(toluene-4-sulfonyl)-propionitrile14,17 was filtered
off and washed with ether (15 mL). Organic layers were
combined and washed successively with water (10 mL), 5%
aqueous KHSO4 (10 mL), water (10 mL), 5% aqueous NaHCO3
(10 mL), and brine (10 mL), dried over anhydrous MgSO4, and
concentrated under reduced pressure. Crude products 5 and 9
were purified by silica gel flash chromatography using increasing
amounts (from 0 to 15% v/v) of AcOEt in Hexanes.
Methyl 2-(tert-Butoxycarbonylamino-phenyl-methyl)acrylate
(5a). This product was obtained after 2 d at room temperature
as a colorless solid (0.99 g) in 68% yield after flash chroma-
1
tography. Mp 77-78 °C; Rf ) 0.53 (hexanes/AcOEt 2:1); H
NMR (250 MHz, CDCl3) δ 7.35-7.25 (m, 5H), 6.38 (s, 1H),
5.92 (s, 1H), 5.68 (brd, 1H, J ) 10.0 Hz), 5.50-5.45 (m, 1H),
3.67 (s, 3H), 1.45 (s, 9H); 13C NMR (63 MHz, CDCl3) δ 165.9,
154.8, 140.0, 139.8, 128.4, 127.3, 126.5, 126.3, 79.6, 55.9, 51.7,
(15) Song, J.; Shih, H.-W.; Deng, L. Org. Lett. 2007, 9, 603.
(16) A mixture of the corresponding (Z/E)-1-[(tert-butoxycarbonyl)ami-
no]propenes (75:25 Z/E) was isolated in 72% yield from the reaction of N-Boc
R-amidoalkyl-p-tolylsulfones 4, derived from propionaldehyde (R ) Et), and
methyl acrylate in the presence of DABCO (1.2 equiv) after 2 weeks at room
temperature.
(14) Achmatowicz, O.; Michalski, J. Rocz. Chem. 1956, 30, 243; Chem Abstr.
1957, 51, 1064.
(17) Kamogawa, H.; Kusaka, H.; Nanasawa, M. Bull. Chem. Soc. Jpn. 1980,
53, 3379.
J. Org. Chem. Vol. 73, No. 21, 2008 8645

28.2; IR (film) 3448, 2976, 1724, 1632, 1492, 1464, 1440, 1392,
1368, 1328, 1272, 1164, 1048, 1024, 956 cm-1; MS m/z (CI,
isobutane) 292 (100%, MH+). Anal. Calcd for C16H21NO4: C,
65.96; H, 7.27; N, 4.81, Found: C, 65.75; H, 6.99; N, 5.00.
acknowledged. The authors wish to express their gratitude
to Miss Julia Frycze for her involvement in this project.
Supporting Information Available: Experimental procedures
and full characterization data for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. Financial support by grant 1T 09A 054
30 from the Ministry of Education and Science is gratefully
JO801616D
8646 J. Org. Chem. Vol. 73, No. 21, 2008