A facile synthesis of cyclic enecarbamates using Dess-Martin periodinane

Article abstract of DOI:10.1016/S0040-4039(01)00998-4

A simple and efficient synthesis of cyclic enecarbamates from ω-hydroxycarbamates via tandem oxidative cyclization-dehydration was achieved in 84% to quantitative yield using Dess-Martin periodinane in methylene chloride.

Full text of DOI:10.1016/S0040-4039(01)00998-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5167–5170
A facile synthesis of cyclic enecarbamates using Dess–Martin
periodinane
Chengzhi Yu and Longqin Hu*
Department of Pharmaceutical Chemistry, College of Pharmacy, Rutgers, The State University of New Jersey,
160 Frelinghuysen Road, Piscataway, NJ 08854-8020, USA
Received 15 May 2001; revised 6 June 2001; accepted 11 June 2001
Abstract—A simple and efficient synthesis of cyclic enecarbamates from v-hydroxycarbamates via tandem oxidative cyclization–
dehydration was achieved in 84% to quantitative yield using Dess–Martin periodinane in methylene chloride. © 2001 Elsevier
Science Ltd. All rights reserved.
There is a growing interest in enecarbamates and enam-
ides in recent years.1 Enecarbamates are used strategi-
cally as intermediates in the assembly of polycyclic
structure motifs in natural products2 and in the devel-
opment of synthetically useful reactions such as
hydroborations and Friedel–Crafts reactions.1 Cyclic
enecarbamates are also versatile building blocks for the
synthesis of bicyclic ring compounds3 and nitrogen-con-
taining heterocycles such as alkaloids.4 Cyclic enecarba-
mates can be prepared by oxidation of carbamates or
N-formyl derivatives to N,O-mixed acetals followed by
the elimination of methyl alcohol5a or its derivative
such as phenylsulfonate.5b Recently, a simple alterna-
tive was developed by reduction of a readily available
lactam followed by dehydration (Scheme 1).5c Although
this method is straightforward and the reduction of
cyclic imides 1 to lactamols 2 is well documented,6
Nagasaka and co-workers found that sometimes the
enecarbamates 3 could not be obtained through the
dehydration of intermediate 2.7 Under the reduction
conditions, compound 2 readily underwent ring-open-
ing with the resulting aldehyde being further reduced to
v-hydroxycarbamate.
group in 4 to the corresponding aldehyde 5 (Scheme 2).
However, several oxidizing conditions we tried failed to
give the desired product 5, but the major product
isolated was cyclic enecarbamate 6. The conditions we
tried and the yields of 6 were as follows: (a) Dess–Mar-
tin periodinane, pyridine, CH2Cl2, rt, 100%; (b) TPAP,
,
NMO, 4 A mole sieves, CH3CN, rt, 72%; (c) DMSO,
(COCl)2, −78°C, THF, then Et3N, −78°C to rt, 65%; (d)
,
PDC, 4 A molecular sieves, CH2Cl2, rt, 59%; and (e)
TEMPO, NaClO (aq.), KBr, CH2Cl2, 0–15°C, 62%.
Dess–Martin periodinane8 was the most efficient condi-
tion giving the cyclic enecarbamate in quantitative
yield. Similar results were reported by Ganem and
co-workers for the oxidation of Cbz-protected v-
hydroxycarbamate using PCC, where no aldehyde but
cyclic enecarbamate was obtained in 46%.9 Rapoport
and co-workers have also found such unexpected
cyclization of d-aldocarbamate to enecarbamate when
they tried to purify the d-aldocarbamate.10
We believe that cyclic enecarbamate product 6 was
formed preferentially through a tandem oxidative
cyclization–dehydration mechanism and that the
cyclization was entropically favored. The oxidation of
v-hydroxycarbamate 4 by Dess–Martin periodinane
In our efforts to synthesize potential protein kinase
inhibitors, we needed to oxidize the primary hydroxy
R
R
R
n
n
n
dehydration
reduction
O
HO
N
N
N
tBoc
tBoc
tBoc
3
1
2
Scheme 1.
* Corresponding author. Tel.: +1 732 445 5291; fax: +1 732 445 6312; e-mail: longhu@rci.rutgers.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00998-4

5168
C. Yu, L. Hu / Tetrahedron Letters 42 (2001) 5167–5170
O
OH
tBoc
[O]
tBoc
OSi(Ph)2But
OCH2OCH3
NH
OSi(Ph)2But
OCH2OCH3
NH
4
5
cyclization
OH
tBoc
tBoc
N
OSi(Ph)2But
OCH2OCH3
dehydration
N
OSi(Ph)2But
OCH2OCH3
6
7
Scheme 2.
and the subsequent cyclization–dehydration were very
mild and efficient. Thus, we optimized the conditions
and developed a general procedure for the preparation
of the synthetically useful cyclic enecarbamates.11
gests that the oxidative cyclization–dehydration was
favored under Dess–Martin periodinane conditions.
Dehydration requires a hydrogen Ca to the aldehyde
group. As expected, compound 14 without the Ca
hydrogen atom could only give the lactamol intermedi-
ate 15 as the major stable product in 88% yield. This
result is consistent with our proposed mechanism
shown in Scheme 2.
As shown in Table 1, various cyclic enecarbamates with
functionalized substitutions could be prepared from
their corresponding v-hydroxycarbamates (4, 8, 10, and
12) in very high yields (84–100%) using this condition.
All products listed were identified by 1H NMR, 13C
NMR, LC–MS, and HRMS.12 In a separate experi-
ment, we found that Swern oxidation13 of v-hydroxy-
carbamate 8 could produce the corresponding aldehyde
1614 in quantitative yield. The fact that Dess–Martin
periodinane-mediated oxidation of 8 gave the cyclic
enecarbamate 9 as the major product (Scheme 3) sug-
To explore what was causing the cyclization and the
subsequent dehydration under the Dess–Martin period-
inane condition, we did two control experiments. In our
first control experiment, a suspension of v-hydroxycar-
bamate 8 and Dess–Martin periodinane in methylene
chloride was stirred at room temperature in the absence
of pyridine. After 24 h, only a small amount of 8
Table 1. The oxidative cyclization–dehydration of v-hydroxycarbamate using Dess–Martin periodinanea

C. Yu, L. Hu / Tetrahedron Letters 42 (2001) 5167–5170
5169
OH
O
tBoc
tBoc
tBoc
Dess-Martin
Swern oxidation
(100%)
N
NH
NH
Periodinane
(92%)
9
8
16
Scheme 3.
Acknowledgements
(<20%) was consumed to produce a complex mixture,
among which we could observe the corresponding alde-
hyde 16 as well as the cyclic enecarbamate 9. This is
consistent with the fact that pyridine is an important
promoting factor in the oxidation using Dess–Martin
periodinane. In our second control experiment, we
added separately acetic acid (2 equiv.), pyridine (2
equiv.), and an equimolar mixture of pyridine (2 equiv.)
and acetic acid (2 equiv.) to a stock solution of alde-
hyde 16 (0.1 M) in methylene chloride. The mixtures
were then stirred under argon at room temperature and
monitored by TLC. Interestingly, we found that the
cyclization–dehydration of aldehyde 16 could be
effected in the presence of either acetic acid (pH 1.3) or
the equimolar mixture of acetic acid and pyridine (pH
4.4). In the presence of acetic acid, the cyclization–
dehydration of 16 to give the cyclic enecarbamate 9 was
faster than that in the presence of equimolar mixture of
acetic acid and pyridine (completion times of 45 min
and 5.5 h, respectively).15 In contrast, there was no
cyclization–dehydration of 16 occurring in the presence
of two equiv of pyridine (pH 8.0) after 24 h. Further-
more, we found that the reaction mixture in the oxida-
tion of 8 quickly turned acidic, with pH dropping down
to about 3.4 after only five minutes of stirring. These
results strongly suggest that the cyclization–dehydra-
tion of 16 was promoted by the acid produced or the
pyridinium ion, the conjugate acid form of pyridine
added. It should be pointed out that the cyclization–
dehydration of aldehyde 16 in the presence of equimo-
lar mixture of acetic acid and pyridine was much slower
than the oxidative cyclization–dehydration of v-
hydroxycarbamate 8 in the presence of Dess–Martin
periodinane and pyridine, suggesting that there might
be other mechanisms involved in the production of
cyclic enecarbamate 9 in addition to the one proposed
in Scheme 3. It should also be noted that the Dess–
Martin periodinane condition did not work for the
formation of five- and seven-membered enecarbamates
from their corresponding hydroxy carbamates. In both
cases, the corresponding aldehydes were found to be
The authors gratefully acknowledge the financial sup-
port of grant GM 62752 from the National Institutes of
Health.
References
1. (a) Ahn, Y.; Cardenas, G. I.; Yang, J.; Romo, D. Org.
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Commun. 1993, 171–172; (b) Boar, R. B.; McGhie, J. F.;
Robinson, M.; Barton, D. H. R. J. Chem. Soc., Perkin
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M. Chem. Rev. 1989, 89, 1525–1534; (d) Padwa, A.;
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J. Chem. 1991, 69, 211–217.
5. (a) Shono, T.; Matsumura, Y.; Tsubata, K.; Sugihara, Y.;
Yamane, S.; Kanazawa, T.; Aoki, T. J. Am. Soc. Chem.
1982, 104, 6697–6703; (b) Brown, D. S.; Charreau, P.;
Hansson, T.; Ley, S. V. Tetrahedron 1991, 47, 1311–1328;
(c) Dieter, R. K.; Sharma, R. R. J. Org. Chem. 1996, 61,
4180–4184.
6. For a review, see: Hiemstra, H.; Speckamp, W. N. In
Comprehensive Organic Synthesis; Heathcock, C. H., Ed.;
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1082.
7. Nagasaka, T.; Tamano, H.; Maekawa, T.; Hamaguchi, F.
Heterocycles 1987, 26, 617–619.
8. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48,
4155–4156; (b) Dess, D. B.; Martin, J. C. J. Am. Soc.
Chem. 1991, 113, 7277–7287; (c) Ireland, R. E.; Liu, L. J.
Org. Chem. 1993, 58, 2899.
9. Tice, C. M.; Ganem, B. J. Org. Chem. 1983, 48, 5043–
5048.
1
the major product as determined by H NMR.
10. Folmer, J. J.; Acero, C.; Thai, D. L.; Rapoport, H. J.
Org. Chem. 1998, 63, 8170–8182.
In summary, we explored the application of Dess–Mar-
tin periodinane in the conversion of v-hydroxycarba-
mates into cyclic enecarbamates via a tandem oxidative
cyclization–dehydration mechanism, avoiding the multi-
step preparation of enecarbamates through lactams and
lactamols. The procedure can accommodate additional
functionality and provides opportunity for the intro-
duction of substituents onto the cyclic enecarbamate
ring systems, thereby making the cyclic enecarbamates
more synthetically accessible.
11. Experimental procedure: To a solution of substrate v-
hydroxycarbamate (1 mmol) in freshly distilled methylene
chloride (10 mL) was added anhydrous pyridine (2
equiv.) and Dess–Martin periodinane (1 equiv.) under
argon at room temperature. The reaction mixture was
stirred for 30 min, quenched with ethyl alcohol (5 mL),
and then diluted with ethyl ether (50 mL). The precipitate
was separated by filtration and washed with ethyl ether
(2×50 mL). The combined filtrate was washed with satu-

5170
C. Yu, L. Hu / Tetrahedron Letters 42 (2001) 5167–5170
rated Na2S2O3–NaHCO3 (1:1, 2×80 mL), dried over
1H), 1.55 (s, 9H), 0.93 (t, J=8.6 Hz, 2H), 0.00 (s, 9H);
13C NMR (CDCl3, 50 MHz): l/ppm 152.2, 124.0, 112.5,
93.4, 87.9, 81.0, 70.4, 65.3, 37.8, 28.5, 18.7, 18.3, −1.23;
ESIMS m/z (relative intensity): 366.35 (M+Na, 98),
198.18 (M−OSEM, 100). HRMS (ESI+) m/z calcd for
C17H33NO4SiNa 366.2077 (M+Na), found 366.2056.
For compound 15: l/ppm 5.17 (d, J=3.6 Hz, 1H), 3.80
(d, J=11.0 Hz, 1H), 3.04 (dt, J=12.8, 3.8 Hz, 1H), 3.00
(d, J=3.5 Hz, 1H), 1.74–1.60 (m, 2H), 1.45 (s, 9H),
1.50–1.40 (m, 1H), 1.26–1.19 (m, 1H), 0.99 (s, 3H), 0.91
(s, 3H); 13C NMR (CDCl3, 50 MHz): l/ppm 155.6, 81.9,
80.0, 38.1, 34.4, 31.3, 28.6, 27.5, 24.1, 21.2; ESIMS m/z
(relative intensity): 212.21 (M−OH, 96), 156.13 (M−
tBuO, 100).
anhydrous MgSO4, filtered, and concentrated under
reduced pressure. The crude product was purified by flash
column chromatography eluting with hexane and ethyl
ether.
1
12. For compound 6: H NMR (CDCl3, 200 MHz): l/ppm
7.74–7.67 (m, 4H), 7.43–7.36 (m, 6H), 6.93 (s, 1H), 4.66
(ABq, Dk=16.7 Hz, J=7.1 Hz, 2H), 4.27 (ABq, Dk=35.7
Hz, J=13.3 Hz, 2H), 4.27–4.15 (m, 1H), 4.02–3.95 (m,
1H), 3.32 (s, 3H), 3.28–3.20 (m, 1H), 2.59 (dd, J=14.5,
3.5 Hz, 1H), 1.82–1.71 (m, 1H), 1.51 (s, 9H), 1.08 (s, 9H);
13C NMR (CDCl3, 50 MHz): l/ppm 152.3, 135.8, 135.8,
133.8, 129.8, 127.8, 127.8, 125.1, 115.6, 95.8, 81.2, 67.3,
64.0, 55.6, 37.3, 28.5, 28.0, 27.1, 19.5; ESIMS m/z (rela-
tive intensity): 512.27 (M+H, 24), 450.25 (M−OMOM,
100). HRMS (ESI+) m/z calcd for C29H41NO5SiNa
534.2652 (M+Na), found 534.2630.
13. It has been reported that Swern oxidation of v-hydroxy-
carbamate 8 gave a complicated mixture including a
substantial amount of aldehyde 16. See: Lee, B. H.;
Miller, M. J.; Prody, C. A.; Neilands, J. B. J. Med. Chem.
1985, 28, 317–323. However, we found under careful
control the same reaction was quite clean and gave high
yield of the aldehyde product 16.
For compound 11: l/ppm 7.74–7.67 (m, 4H), 7.49–7.7.36
(m, 6H), 6.93 (s, 1H), 4.71 (ABq, Dk=15.0 Hz, J=7.4
Hz, 2H), 4.28 (ABq, Dk=32.4 Hz, J=14.0 Hz, 2H),
4.35–4.15 (m, 1H), 4.03–3.94 (m, 1H), 3.60 (t, J=8.4 Hz,
2H), 3.26 (t, J=11.7 Hz, 1H), 2.10 (d, J=13.5 Hz, 1H),
1.80–1.65 (m, 1H), 1.51 (s, 9H), 1.09 (s, 9H), 0.91 (s,
J=8.6 Hz, 2H), 0.00 (s, 9H); 13C NMR (CDCl3, 50
MHz): l/ppm 152.3, 135.8, 135.8, 133.8, 129.8, 127.8,
127.8, 125.1, 115.6, 94.0, 87.9, 81.2, 67.4, 65.3, 64.0, 37.2,
28.5, 27.1, 19.5, 18.2, 1.25; ESIMS m/z (relative inten-
sity): 598.34 (M+H, 47), 524.27 (M−tBuO, 100). HRMS
(FAB+) m/z calcd for C33H51LiNO5Si2: 604.3466 (M+Li).
Found: 604.3478.
14. For aldehyde 16: 1H NMR (CDCl3, 200 MHz): l/ppm
9.78 (s, 1H), 4.62 (br s, 1H), 3.13 (dd, J=13.0, 6.6 Hz,
2H), 2.61–2.45 (m, 2H), 1.73–1.44 (m, 13H, singlet at 1.45
(3H)); 13C NMR (CDCl3, 50 MHz): l/ppm 202.4, 156.2,
79.3, 43.6, 40.3, 29.7, 28.6, 19.3; IR (neat): w 3354, 2964,
2923, 2862, 2810, 2718, 1708 cm−1
.
15. For similar Lewis acid-mediated cyclization and elimina-
tion of methanol from mixed acetals, see: (a) Corey, E. J.;
Kang, M.-C.; Desai, M. C.; Ghosh, A. K.; Houpis, I. N.
J. Am. Chem. Soc. 1988, 110, 649–651; (b) Kozikowski,
A. P.; Ghosh, A. K. J. Org. Chem. 1985, 50, 3017–3019.
For compound 13: l/ppm 6.63 (s, 1H), 4.74 (ABq, Dk=
24.5 Hz, J=7.3 Hz, 2H), 3.91–3.52 (m, 4H), 3.18–3.15
(m, 1H), 2.01–1.94 (m, 1H), 1.75 (s, 3H), 1.74–1.60 (m,
.