p-Nitrophenyl carbonate promoted ring-opening reactions of DBU and DBN affording lactam carbamates

Article abstract of DOI:10.3762/bjoc.12.197

The amidine bases DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) and DBN (1,5-diazabicyclo[4.3.0]non-5-ene) display nucleophilic behaviour towards highly electrophilic p-nitrophenyl carbonate derivatives with ring opening of the bicyclic ring to form correspond

Full text of DOI:10.3762/bjoc.12.197

p-Nitrophenyl carbonate promoted ring-opening reactions of
DBU and DBN affording lactam carbamates
Madhuri Vangala* and Ganesh P Shinde
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 2086–2092.
Department of Chemistry, Indian Institute of Science Education and
Research, Pune 411 008, India
doi:10.3762/bjoc.12.197
Received: 08 July 2016
Email:
Accepted: 06 September 2016
Published: 26 September 2016
Madhuri Vangala* - madhuri@iiserpune.ac.in
* Corresponding author
Associate Editor: J. S. Dickschat
Keywords:
© 2016 Vangala and Shinde; licensee Beilstein-Institut.
License and terms: see end of document.
carbonates; DBN; DBU; lactams; p-nitrophenyl
Abstract
The amidine bases DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) and DBN (1,5-diazabicyclo[4.3.0]non-5-ene) display nucleophilic
behaviour towards highly electrophilic p-nitrophenyl carbonate derivatives with ring opening of the bicyclic ring to form corre-
sponding substituted ε-caprolactam and γ-lactam derived carbamates. This simple method presents a unified strategy to synthesize
structurally diverse ε-caprolactam and γ-lactam compounds with a large substrate scope.
Introduction
Among various organic bases, amidines such as DBU derivatives of main group elements where the DBU and DBN
(1,8-diazabicyclo[5.4.0]undec-7-ene) and DBN (1,5-diazabi- bicyclic rings remained unaffected [10,11]. Later in 1994,
cyclo[4.3.0]non-5-ene) having an imino group attached to the Lammers et al. observed the nucleophilicity of amidine bases
α-carbon of the amine are synthetically useful and strong with 4-halo-3,5-dimethyl-1-nitro-1H-pyrazole and their subse-
neutral bases. Besides, DBU and DBN catalyze various organic quent ring opening leading to the lactam products [12]. Subse-
reactions such as dehydrohalogenations [1], carbonylations [2], quently, Ma and Dolphin isolated chlorin-e6 lactams from the
amidations [3] and Baylis–Hillman reactions [4]. These bicyclic reaction of methyl pheophorbide with DBU and DBN promoted
amidines have been thought to be non-nucleophilic bases, but by trialkyl triflates [13]. Additionally, the conjugate addition
meanwhile numerous examples unveiled their ability to act as C reaction of DBU to diarylpyrone [14] and Baylis–Hillman
and N nucleophiles [5-8]. In 1981, McCoy and Mal first isolat- acetates [15] also gave caprolactam products. A closer look at
ed an adduct of DBU with dimethyl 1-chloro-3-methyl cyclo- these results suggested that the nucleophilic behavior of DBU
propane-1,2-dicarboxylate during the dehydrohalogenation of highly depends on specific substrates. Vaidyanathan and
halocyclopropanes [9]. In 1993, Bertrand and co-workers, co-workers reported the DBU-catalyzed addition of amines to
showed that DBU and DBN act as nucleophiles towards halo acyl imidazoles [16], however, using a stoichiometric amount of
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DBU, Rajagopal et al. observed nucleophile behavior of DBU hexanol (Table 1, 1a) in THF, exclusively afforded the ε-capro-
towards imidazolides providing ε-caprolactam-derived carba- lactam product 1b when 2 equiv of DBU were used. After 1 h
mates and amides [17]. Here, in this report we present the reaction at room temperature almost all starting material was
results obtained by the reaction of DBU and DBN with highly consumed (90%, TLC) and heating the reaction mixture to
electrophilic p-nitrophenyl carbonates leading to ε-caprolactam 60 °C led to complete consumption of the starting material
and γ-lactam carbamates.
within 1 h to give product 1b. The transformation involves a
nucleophilic attack of the imine nitrogen onto the carbonyl car-
p-Nitrophenyl carbonates are highly reactive compounds that bon followed by the elimination of a p-nitrophenoxide ion.
are usually treated with alcohols or amines to give either a new Subsequently, the imine carbon of DBU is attacked by water
carbonate or a carbamate-linked compound depending on the molecules present in the solvent, leading to the ring opening
nucleophile. In one of our earlier reports, polycarbamate nucleic and formation of the corresponding caprolactam carbamates
acids were synthesized from p-nitrophenyl carbonates with (Scheme 1).
amines of nucleic acid derivatives [18]. Very recently, Hotha et
al. utilized 1-ethynylcyclohexyl p-nitrophenyl carbonate to The structure of 1b was confirmed by 1H and 13C spectroscopy,
synthesize alkynyl glycosyl carbonate donors from hemiacetals which showed the characteristic carbamate NH triplet at
[19]. Also, glycocarbamates [20] obtained from glycosyl 5.80 ppm in the 1H NMR spectrum and the expected peaks at
p-nitrophenyl carbonates [21-24], were explored in studies of 176.6 and 155.0 ppm in the 13C NMR spectrum for the capro-
carbohydrate–protein interactions [25], ligation and surfactant lactam and carbamate carbonyl carbons, respectively. Addition-
properties [26,27]. Although p-nitrophenyl carbonates were ex- ally, HRMS and IR absorptions of the carbonyl groups at 1713,
tensively utilized in these reactions, the nucleophilicity of 1624 and carbamate NH at 3301 cm−1 also confirmed the ring
amidine bases towards these carbonates was not encountered so opening of DBU. Excited with the outcome of the reaction, we
far. In continuation of our interest in carbohydrates [28,29] and set out to explore the structural diversity using different p-nitro-
the synthesis of carbamate-linked compounds using p-nitro- phenyl carbonates which were prepared by treating an alcohol
phenyl carbonates, we herein report our results from nucleo- with p-nitrophenyl chloroformate in CH2Cl2 using pyridine as a
philic ring opening reactions of DBU and DBN using p-nitro- base. Thus, homopropargyl alcohol, decanol, cholesterol and
phenyl carbonates.
N-Boc-trans-4-hydroxy-L-proline methyl ester gave the corre-
sponding carbonates (Table 1, 2a–5a) in good to excellent
yields. Subsequently, the purified carbonates dissolved in THF
Results and Discussion
In the course of this study, we observed that in the absence of a were treated with 2 equiv of DBU. Heating the reaction mix-
nucleophile the p-nitrophenyl carbonate of 1-ethynylcyclo- ture to 60 °C for 1 h gave the caprolactam carbamate products
Scheme 1: Reaction of DBU with p-nitrophenyl carbonate.
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Table 1: Synthesis of ε-caprolactam-derived carbamates 1b–8b.
No
1
carbonate
product
yield
85%
1a
2a
1b
2b
3b
2
3
79%
88%
3a
4
69%
4b
4a
5a
5
71%
5b
6
82%
6a
6b
7
8
87%
48%
7a
8a
7b
8b
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Beilstein J. Org. Chem. 2016, 12, 2086–2092.
2b–5b along with p-nitrophenol as byproduct. In case of the As DBU and DBN are known to promote dehydrohalogenation
ε-caprolactam of N-Boc-trans-4-hydroxy-L-proline methyl ester reactions, we turned our attention to halogenated alcohols.
5b, rotamers due to flipping of the N-Boc group were obtained. Thus, the p-nitrophenyl carbonate of 10-bromo-1-decanol 14a
Owing to the importance of sugar caprolactams in polymeriza- was reacted with DBN at 60 °C for 1 h affording a single polar
tions, 2,3-di-O-benzyl-4-O-p-methoxybenzyl-α-methyl-D- spot on TLC. To our surprise, the 1H NMR spectrum showed
glucopyranoside and 2,3,4-tri-O-benzoyl-α-methyl-D-gluco- the existence of two compounds with the carbamate NH
pyranoside [30,31] were converted into the p-nitrophenyl showing a multiplet rather than a triplet and an additional signal
carbonates 6a and 7a in good yields. The corresponding for the p-nitrophenyl group. In the 13C NMR spectrum, peaks at
carbonate of per-O-benzoyl glucopyranose 8a [30,31] was ob- 175.7 and 157.0 ppm for the cyclic amide and carbamate car-
tained in only moderate yield and as a mixture of α and β bon confirmed the ring opening of DBN. However, the appear-
anomers which was used without further purification. The ance of new peaks in the 13C NMR at 164.3, 141.2 and
carbonates were subsequently reacted with DBU under the same 126.0 ppm and the upfield shift of C2 of p-nitrophenyl substitu-
conditions as described above, giving 6b and 7b in 82% and ent from 122 ppm to 114.4 ppm, suggested that DBN displaced
87% yield, and 8b as a mixture of α and β anomers in 48% a bromide with the p-nitrophenoxide ion to give compound 14c.
yield. Encouraged by these results, we turned to evaluate the Thus, DBN played a dual role in the reaction with 14a – namely
nucleophilicity of DBN towards p-nitrophenyl carbonate deriva- as nucleophile and as base giving products 14b and 14c in a 1:1
tives (Scheme 2).
ratio. The peaks at 164.3 and 114.4 ppm can therefore be
assigned to the ipso carbon and ortho carbon of the p-nitro-
phenyl substituent in 14c. This observation was particularly
interesting as N-alkylation of DBN [36] was not favored and
instead underwent substitution. To test if the reaction favors
both – nucleophilic addition as well as substitution – at lower
temperature, the reaction was performed at room temperature
for 1.5 h. Although both products were observed the substitu-
tion product was minor product, as seen by the integration of
p-nitrophenol peaks in the 1H NMR. On the contrary, the reac-
tion of the 2-(2-chloroethoxy)ethanol carbonate 15a with DBN
at room temperature and at 60 °C gave only the ring-opened
product of DBN 15b in 30% and 41% yield, due to the poor
leaving ability of chloride relative to bromide. Further, addition
Scheme 2: Reaction of DBN with p-nitrophenyl carbonates.
Next, the reaction of the p-nitrophenyl carbonate of homo- of DBN to the acidic-proton containing substrates such as the
propargyl alcohol 2a in THF with 2 equiv of DBN was exam- p-nitrophenyl carbonate of 9-fluorenemethanol 16a and N-Cbz-
ined. Similar to the results observed with DBU, more than 90% L-serine methyl ester 17a, resulted in the dibenzofulvene prod-
of the reaction was complete at room temperature in 1 h. How- uct 16b in the former, and a mixture of products in the latter,
ever, heating the reaction mixture to 60 °C for 1 h resulted in with DBN acting as a base. Even though the γ-lactam products
completion of the reaction giving the γ-lactam carbamate 2ab in were the only major compounds noticed, the yields were sub-
56% yield (Table 2). The 1H NMR spectrum of the product 2ab stantially lower than the caprolactam products, presumably due
showed a broad singlet at 5.70 ppm assigned to the carbamate to the ease of ring opening of DBU.
NH. The corresponding peaks at 175.6, 156.3 ppm in the
13C NMR spectrum as well as the HRMS and IR data con- To check if the nucleophilicity of DBU/DBN was specific to the
firmed the ring opening of DBN. To evaluate the substrate highly electron deficient p-nitrophenyl carbonate, a set of three
feasibility, one phenol, an allylic alcohol and three sugar alco- different carbonates of 1-ethynylcyclohexanol were synthe-
hols were subjected to the reaction. The 3,4-dimethylphenyl sized using phenyl, benzyl and ethyl chloroformate, respective-
p-nitrophenyl carbonate (9a) and geranyl carbonate 10a gave ly. The reaction of the phenyl carbonate (Table 3, A) with DBU
the corresponding γ-lactams 9b and 10b in 62% and 46% at 60 °C for 20 h gave ε-caprolactam (1b) with 12% yield. In
yields, respectively. Similarly, the p-nitrophenyl carbonate of contrast, in the reaction of benzyl and ethyl carbonates (B, C)
D-psicofuranose [28], n-pentenyl 2,3,4-tri-O-benzyl-α-D- with DBU no trace of lactam (1b) was formed and the sub-
mannopyranoside [32-34] and 2,3-di-O-benzyl-α-methyl-D- strates remained unaffected due to the poor leaving nature of the
arabinofuranoside [35] (Table 2, 11a–13a) gave the γ-lactam- alkoxides in comparison to phenolates. This suggests that a
derived carbamates 11b–13b in 53%, 63% and 67% yield, re- highly electrophilic center is the prerequisite for the nucleo-
spectively.
philic behavior of DBU and DBN to come into play.
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Table 2: Synthesis of γ-lactam-derived carbamates 2ab, 9b–16b.
No
1
carbonate
product
yield
56%
2a
2ab
2
62%
9a
9b
3
4
46%
53%
10a
10b
11a
11b
5
6
63%
67%
12a
13a
12b
13b
14b
14c
7
8
64%
14a
15a
41%a
30%b
15b
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Beilstein J. Org. Chem. 2016, 12, 2086–2092.
Table 2: Synthesis of γ-lactam-derived carbamates 2ab, 9b–16b. (continued)
9
16b
16a
10
mixture of products
17a
areaction at 60 °C and bat rt.
Table 3: Reactivity of different carbonates with DBU.
R = PhNO2 (1a)
R = Ph (A)
R = CH2Ph (B)
R = C2H5 (C)
Product 1b 85%
Product 1b 12%
no rxn
no rxn
(60 °C, 1 h)
(60 °C, 20 h)
(60 °C, 20 h)
(60 °C, 20 h)
Finally, nearly quantitative large scale transformations were Acknowledgements
achieved, when 3.5 g of substrates 3a and 7a were reacted with MV is grateful to Prof. K. N. Ganesh, IISER Pune for research
DBU at 60 °C for 1 h giving lactams 3b and 7b in 90% and support and infrastructural facilities and Dr. Srinivas Hotha for
94% yield, respectively.
helpful discussions and lab facility. MV thanks DST SERB,
India for Fast Track research grant (SB/FT/CS-159/2012). GPS
thanks UGC, New Delhi for Junior Research Fellowship.
Conclusion
In conclusion, we have shown an operationally simple synthe-
sis of carbamate-derived ε-caprolactam and γ-lactam com-
pounds utilizing the nucleophilicity of DBU/DBN and highly
electrophile p-nitrophenyl carbonate derivatives. The reactions
proceeded even at room temperature and displayed the nucleo-
philic addition and substitution with the p-nitrophenyl carbonate
derivative of 10-bromodecanol. These caprolactam derivatives
may find application in polymer chemistry.
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