Photochemical rearrangement of N-mesyloxylactams: Stereospecific formation of N-heterocycles

Article abstract of DOI:10.1021/jo101805q

N-Mesyloxylactams undergo an efficient ring-contraction to N-heterocycles of various ring sizes. Yields increase with the degree of substitution α to the carbonyl. The stereochemical information of a chiral migrating carbon is conserved making this reacti

Full text of DOI:10.1021/jo101805q

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Photochemical Rearrangement of N-Mesyloxylactams:
Stereospecific Formation of N-Heterocycles
Alexandre Drouin, Dana K. Winter, Simon Pichette, Samuel Aubert-Nicol,
Jean Lessard,* and Claude Spino*
ꢀ ꢀ ꢀ ꢀ
Departement de Chimie, Universite de Sherbrooke, 2500 boul. Universite, Sherbrooke, Quebec, Canada, J1K 2R1
jean.lessard@usherbroke.ca; claude.spino@usherbrooke.ca
Received September 17, 2010
N-Mesyloxylactams undergo an efficient ring-contraction to N-heterocycles of various ring sizes.
Yields increase with the degree of substitution R to the carbonyl. The stereochemical information of a
chiral migrating carbon is conserved making this reaction a synthetically useful complement to the
well-known Hofmann, Curtius, Lossen, and Schmidt rearrangements.
Introduction
of medicinal and synthetic chemistry.1 Alkaloids comprising
N-heterocycles where the nitrogen atom is flanked by one or two
chiral carbons have attracted special attention because of the
number of biologically active compounds that possess this
structural feature and also because they are particularly chal-
lenging molecular targets for synthesis. A variety of methods
exist for the synthesis of N-heterocycles that is inventoried in
several reviews2 and books.3
The well-known Schmidt, Hofmann, Curtius, and Lossen
rearrangements have been used extensively to create a C-N
bond from a C-C bond in a stereospecific fashion.4 Thus far, all
of these methods can only transform primary acyclic acyl azides
or amide derivatives 1a-c to carbamate 2 (Scheme 1), with the
exception of the Hofmann rearrangement of cyclic imides,
which, in any case, probably involves an acyclic intermediate.5
We have previously reported a novel photochemical ring-
contraction of N-chlorolactams 3b (X =Cl) toN-heterocycles 4
in yields ranging from 5% to 56% (Scheme 1).6 By contrast to
The key biochemical roles played by alkaloids in nature make
this class of molecules the center of intense research in the fields
(1) For selected books and reviews, see: (a) Hesse, M. In The Alkaloids,
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Nature’s Curse or Blessing?; Wiley VCH: Zurich, Switzerland, 2002; pp 1-413.
(b) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139-165. Cordell, G. A. In The
Alkaloids: Chemistry and Biology; Elsevier: San Diego, CA, 2003; Vol. 60,
pp 1-282. (c) Kobayashi, J.; Morita, H. Alkaloids 2003, 60, 165–205.
(d) Yamamura, S. In The Alkaloids; Brossi, A., Ed.; Academic Press:
New York, 1986; Vol. 29, 265 pp. (e) Moldvai, I.; Temesvari-Major, E.; Incze,
M.; Doernyei, G.; Szentirmay, E.; Szantay, C. Helv. Chim. Acta 2005, 88, 1344–
1356. (f ) Reynolds, T. Phytochemistry 2005, 66, 1399–1406. (g) Lewis, J. R. Nat.
Prod. Rep. 2001, 18, 95–128.
(2) (a) Martin, S. F. Pure Appl. Chem. 1997, 69, 571–576. (b) Kunz, H.;
Pfrengle, W. Angew. Chem., Int. Ed. 1989, 28, 1067–1068. (c) Pearson, W. H.
Pure Appl. Chem. 2002, 74, 1339–1347. (d) Fox, D. J.; House, D.; Warren, S.
Angew. Chem., Int. Ed. 2002, 41, 2462–2482. (e) Fu, G. C.; Grubbs, R. H.
J. Am. Chem. Soc. 1992, 114, 7324–7325. (f ) Shibata, I.; Kato, H.; Kanazawa,
N.; Yasuda, M.; Baba, A. J. Am. Chem. Soc. 2004, 126, 466–467. (g) Dieters,
A.; Martin, S. F. Chem. Rev. 2004, 104, 2199–2238. (h) Zeni, G.; Larock,
R. C. Chem. Rev. 2006, 106, 4644–4680. (i) Stanovnik, B.; Svete, J. Chem.
Rev. 2004, 104, 2433–2480. ( j) Jagodzinski, T. S. Chem. Rev. 2003, 103, 197–
228. (k) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285–2310.
(l) Barluenga, J.; Santamaria, J.; Tomas, M. Chem. Rev. 2004, 104, 2259–2284.
(3) (a) Fattorusso, E.; Taglialatela-Scafati, O. In Modern alkaloids; struc-
ture, isolation, synthesis and biology; WILEY-VCH, Weinheim, Germany, 2008;
pp 1-665. (b) van der Eycken, E.; Kappe, C. O. In Microwave-Assisted Synthesis
of Heterocycles, 1st ed.; Springer: Paris, France, 2006; pp 1-309. (c) Padwa, A.;
Pearson, W. H. In Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry
Toward Heterocycles and Natural Products, 1st ed.; WILEY-Interscience:
London, UK, 2002; pp 1-952. (d) El Ashry, E. S. H.; El Nemr, A. In Synthesis
of Naturally Occurring Nitrogen Heterocycles from Carbohydrates, 1st ed.;
WILEY-Blackwell: Oxford, UK, 2005; pp 1-464. (e) Eicher, T.; Hauptmann,
S.; Suschitzky, H. In The Chemistry Of Heterocycles: Structure, Reactions,
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2002; pp 1-514.
(4) (a) Banthorpe, D. V. In The Chemistry of the Azido Group; Patai, S.;
Wiley: New York, 1971; pp 1-626. (b) Walis, E. S.; Lane, J. F. Org. React.
1946, 3, 267–306. (c) Wolff, H. Org. React. 1946, 3, 307–336. (d) Smith,
P. A. S. Org. React. 1946, 337–449. (e) Senanayake, C. H.; Fredenburg, L. E.;
Reamer, R. A.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. J. Am. Chem.
Soc. 1994, 116, 7947–7948. (f ) Gogoi, P.; Konwar, D. Tetrahedron Lett.
2007, 48, 531–533. (g) Bauer, L.; Exner, O. Angew. Chem., Int. Ed. 1974, 13,
376. (h) Lang, S.; Murphy, J. A. Chem. Soc. Rev. 2006, 35, 146–156.
(5) See, for example: Jianga, X.; Wanga, J.; Hua, J.; Gea, Z.; Hua, Y.;
Hua, H.; Covey, D. F. Steroids 2001, 66, 655–662.
(6) (a) Drouin, A.; Lessard, J. Tetrahedron Lett. 2006, 47, 4285–4288.
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164 J. Org. Chem. 2011, 76, 164–169
Published on Web 12/03/2010
DOI: 10.1021/jo101805q
r
2010 American Chemical Society

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SCHEME 1. Schmidt-Like Rearrangements and the Ring-
Contraction of N-Heterosubstituted Lactams
with wet methanol (15% water) with, as a consequence, a lower
yield of the desired products (10-20% decrease in yields) and
the formation of some unidentified decomposition products.
At -78 °C, the yields were higher by 40% and 30%, respec-
tively, than those obtained from the corresponding N-chloro-
lactams.6b The very fact that we could run the reaction in
methanol hints to the absence of free radicals in the solution. In
addition, a constant bubbling of oxygen through the reaction
mixture had no noticeable effect on the outcome of the reaction.
The rearrangement of N-chlorolactams was best run in dichloro-
methane and could not be performed in solvents like metha-
nol, presumably due to fast hydrogen abstraction from a C-H
bond by a chlorine radical. Piperidines 19 and 20 were obtained
from the photochemical ring-contraction of 7-membered
N-mesyloxylactams 7c and 8c (entries 3 and 4). Azepane 21 was
obtained in 56% yield from the corresponding 8-membered
N-mesyloxylactam 9c (entry 5).
the Lossen rearrangement, only cyclic or polycyclic structures
like 3 undergo rearrangement in this photochemical ring-
contraction. Importantly, chirality at the migrating carbon in 3is
wholly retained in the ring-contraction product 4. The comple-
mentary nature of our rearrangement to the Lossen rearrange-
ment makes it a highly desirable transformation for organic
chemists. Some advantages include the ease of construction of
N-substituted lactams from the cyclization of carboxylic acid
and amine derivatives,7 and the ease of introduction of chirality
R to carbonyls.8 Yet, the low yields (usually <40%) of the de-
sired products 4 from 3b (X=Cl) represented a major obstacle
to the application of this methodology in synthesis. The parent
amide 3a (X=H) and chlorinated byproduct account for the
remaining material, owing to the presence of chlorine radical.6b
We therefore investigated alternative N-substituents in order to
prevent the formation of such byproduct in the hope of aug-
menting the yield of the desired product 4. We now report that
the photochemical ring contraction of O-mesylated hydroxamic
acids 3c (X=OMs) gives high yields of the desired ring-
contracted N-heterocycles 4unaccompanied by the parent amide
or byproduct derived from radical pathways.9 This rearrange-
ment is unique,10,11 and now represents a useful complement
to the arsenal of existing methods for the synthesis of chiral
N-heterocycles.
As was the case for the analogous N-chlorolactams, a
higher substitution at the migrating carbon led to a higher
yield of rearrangement product (compare entries 1 and 2 as
well as 3 and 4). However, the yield of 19 (entry 3) is much
higher than expected since irradiation of the homologous N-
chlorolactam 7b (structure 7c with OMs = Cl) gave only a
6% yield of rearranged product 19.6
The result of entry 3 compelled us to try the photochemical
rearrangement of acyclic N-mesyloxyamide 30c and to our
great surprise, an 18% yield of rearranged product 31 was
obtained, along with 60% of the expected10 N-acyl hemi-
aminal ether 32 (Scheme 2). The analogous N-chlorolactam
30b (OMs = Cl) gave no trace of the rearranged product 31,
36% of the parent amide 30a (OMs = H), 23% of product
32, and several other products (see the Supporting Informa-
tion). In fact, acyclic N-chloroamides have never yielded
rearrangement products under our irradiation conditions.
To the best of our knowledge, this is the first example of a
rearrangement involving an acyclic secondary amide deriva-
tive of any kind. We are further exploring the scope of this
reaction for acyclic amide derivatives.
Rigid bicyclic compounds are good substrates for the
rearrangement as the yield of product 22 from N-mesyloxy-
lactam 10c suggests (entry 6). Contrary to what was found in
the photochemical ring-contraction of the corresponding
N-chlorolactams, the parent amides 5a-16a (OMs=H) were
never detected after photolysis, which is, again, indicative of
the absence of radical pathways.6b The mechanism of the
reaction is still unclear but we believe that either an excited state
3* decays directly to the rearranged product 40 (Scheme 3) or
that homolytic cleavage to 30 occurs followed by either electron
transfer with concomitant rearrangement to 40 from a tight
radical pair or electron transfer to the ion pair 300, which we
deem unlikely. If one of the electron transfer pathways is
operative, the electron transfer must occur before the mesyloxy
radical in 30 escapes from the solvent cage, thus faster than in the
case of the N-chlorolactams.10 Methanol then reacts with the
intermediate 40 to give the final product 4.
Results and Discussion
The photochemical ring contractions of 6-membered
N-mesyloxylactams 5c and 6c were carried out at 254 nm in
anhydrous methanol at -78 °C. To our delight, pyrrolidines 17
and 18 were obtained in useful yields (Table 1, entries 1 and 2).
The photolysis can be carried out at room temperature and/or
(7) Ogliaruso, M. A.; Wolfe, J. F. In Synthesis of Lactones and Lactams;
John WILEY & Sons Inc.: Hoboken, NJ, 1993; pp 1-1100 and references
cited therein.
(8) For reviews, see: (a) Arya, P.; Qin, H. Tetrahedron 2000, 56, 917–947.
and references cited therein. (b) Spino, C. Org. Prep. Proced. Int 2003, 35,
1–140.
(9) See the Supporting Information for the synthesis of the N-mesyloxy
lactams.
Photolysis of O-mesyloxylactam 11c in dichloromethane
followed by a methanolic treatment yielded a 71% yield of 23
and 12% of 34 (entry 7 and Scheme 3). When carried out in
methanol, carbamate 23 was obtained in only 48% yield
from irradiation of 11c, accompanied by 51% of the linear
acetal 34. Irradiation in methanol of N-mesyloxylactam 12c,
bearing a less electron-donating acetate on the migrating
(10) Edwards et al. have reported that the photolysis of N-mesyloxy-
4-aza-cholestane-3-one in methanol at room temperature gave the undesired
ring contracted carbamate in 35% yield besides several other products. To
the best of our knowledge, no further study of this reaction has been reported
since. See: Edwards, O. E.; Grue-Sorensen, G.; Blackwell, B. A. Can.
J. Chem. 1997, 75, 857–872.
(11) Di Maio and Tardella have reported two low-yielding examples of
thermal ring-contraction of hydroxamic acid in phosphoric acid at 180 °C.
See: DiMaio, G.; Tardella, P. A. Proc. Chem. Soc. 1963, 224.
J. Org. Chem. Vol. 76, No. 1, 2011 165

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TABLE 1. Results Obtained from the Irradiation of N-Mesyloxylactams 5c-16c of Varying Ring Sizes
aReaction conditions: MeOH, 254 nm, -78 °C, Et3N. bIsolated yields. cConditions: (i) DCM, 254 nm, -78 °C;(ii) MeOH, Et3N. dSee Scheme 3. eConditions:
(i) DCM, Et3N, 254 nm, -78 °C; (ii) MeOH. fThe isomeric rearrangement products 28 (20%, entry 10) and 29 (19%, entry11) were also isolated.
166 J. Org. Chem. Vol. 76, No. 1, 2011

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SCHEME 2. Rearrangement of Acyclic N-Mesyloxylactam 30c
SCHEME 4. Stereospecific Rearrangement of cis- and trans-35
SCHEME 3. Mechanistic Pathways for the Formation of Prod-
uct 4 or Acetal 34
Importantly, the rearrangement of N-mesyloxylactams is
stereospecific and occurs with complete retention of stereo-
chemistry at the migrating carbon. Indeed, racemic syn-35c
and anti-35c each gave a single diastereomer syn-36 and anti-
36, respectively (Scheme 4).
The photochemical ring-contraction of six- to eight-
membered N-mesyloxylactams constitutes a unique and synthet-
ically useful route to N-heterocycles. Generally speaking,
6-membered N-substituted lactams rearrange in slightly
higher yields than their 7- or 8-membered counterpart,
and higher substitution R to the amide carbonyl leads
to increased yields. The method is complementary to the
Lossen and related rearrangements, and should be a useful
addition in the arsenal of the synthetic chemist. Mechan-
istic as well as synthetic explorations of this reaction are
presently underway and will be reported in due course.
carbon, afforded 65% yield of 23, along with 30% yield of 34
(entry 8). The substitution of acetate for a methoxy group in
this experiment indicates that the reaction medium becomes
acidic upon irradiation. Though the mechanistic details of
this fragmentation are still unknown, it is probable that ring
cleavage to intermediate 33a or 33b is in competition with the
ring contraction pathway leading to 23. It is also probable
that the increased polarity of methanol as compared to
dichloromethane favors the formation of the charged species
33a or 33b. This fragmentation is analogous to the abnormal
Beckmann rearrangement.12
Two spirocyclic N-mesyloxylactams 13c and the more com-
plex 14c rearranged efficiently to isoindolines 24 and 25, respec-
tively (entries 9 and 10). In this particular case, the rearrange-
ment product 24 was sensitive to light and decomposed upon
prolonged exposure to irradiation, which explains the lower
than expected yield. Again, the increasing acidity of the solution
upon irradiation is probably responsible for the cleavage of the
acetonide group in the case of 14c. Strangely, the addition of
base (triethylamine) during irradiation had little effect on the
yield of rearrangement and on the cleavage of the acetonide.
Lastly, bicyclic products 26 and 27 were formed in 47%
and 54% yield, respectively (entries 11 and 12). These yields
are quite impressive considering that there is no substitution
R to the carbonyl in these two cases. In each of these two
particular cases, a product from the migration of the
angular quaternary carbon was also isolated (see footnote
f of Table 1). The latter are rarely seen and we are currently
looking at structural features of the precursors that may
favor this migration.
Experimental Section
Methyl 2-Benzylazepane-1-carboxylate (21). A solution of the
mesylated hydroxamic acid 9c (18 mg, 0,058 mmol) in anhydrous
MeOH at -78 °C was placed in a quartz cell and irradiated at 254 nm
until no more starting material was seen. After 5 h the reaction
was warmed to room temperature and 1 mL of Et3N was added to
the mixture. After 1 h at room temperature the mixture was concen-
trated under reduced pressure. The crude mixture was purified on
silica gel, eluting with 1:9 EtOAc/hexanes. Methylcarbamate 21
(8 mg, 0,03 mmol, 56% yield) was recovered as a colorless oil.
1H NMR (300 MHz, CDCl3) δ(ppm) rotamer A: 7.29-7.10 (m, 5H),
4.30-4.17 (m, 1H), 3.70 (s, 3H), 3.66 (br d, 1H, J=12.9 Hz), 2.87
(dd, 1H, J1=12.9 Hz, J2=4.7 Hz), 2.78-2.57 (m, 2H), 1.97-1.56
(m, 4H), 1.50-1.10 (m, 4H); rotamer B: 7.29-7.10 (m, 5H), 4.10
(hex, 1H, J=6.0 Hz), 3.85 (br d, 1H, J=14.1 Hz), 3.52 (s, 3H),
2.78-2.57 (m, 3H), 1.97-1.56 (m, 4H), 1.50-1.10 (m, 4H). 13C
NMR (75.5 MHz, CDCl3) δ (ppm) (rotamers noted with*) 157.0,
138.8, 129.4, 129.3*, 128.2, 126.1, 57.5, 57.3*, 52.4, 52.2*, 42.0, 41.5,
41.0, 33.6, 32.7, 29.7, 29.6*, 28.9, 25.1. LRMS (m/z, rel intensity)
248 ([MH]þ, 1), 216 (40), 157 (80), 102 (80), 86 (80), 84 (100).
HRMS calcd for C15H21NO2 247.1572, found 247.1577. IR
(CHCl3) ν (cm-1) 3067, 3022, 2976, 2897, 1671.
Methyl 2-Methoxypyrrolidine-1-carboxylate (23) and Methyl
4,4-Dimethoxybutylcarbamate (34) From 11c. N-mesylate 11c
(97.0 mg, 0.435 mmol) was dissolved with anhydrous dichloro-
methane (29 mL) and added into a Rayonet reactor chamber
equipped with 254 nm UV lamps. The reaction mixture was then
exposed to UV light at -78 °C under N2 atmosphere until com-
pletion (1.5 h). The solution was then transferred to a stirring
solution of MeOH (5 mL) and triethylamine (61 μL, 0.435 mmol)
and left stirring for 16 h. The solution was then concentrated under
reduced pressure to a light yellow oil. The oil was partitioned
(12) Bzaszczyk, K.; Koenig, H.; Mel, K.; Paryzek, Z. Tetrahedron 2006,
62, 1069–1078. and references cited therein.
J. Org. Chem. Vol. 76, No. 1, 2011 167

Drouin et al.
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between dichloromethane (50 mL) and H2O (50 mL). The aqueous
was extracted twice more with dichloromethane (25 mL). The
organic layers were combined, dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure to a clear oil.
The oil was taken up in dichloromethane and purified by flash
chromatography with a 1:1 to 9:1 ether/hexanes solvent system to
yield 23 as clear oil (48.9 mg, 71%). The acetal 34 (9.8 mg, 12%)
was also isolated as a colorless oil.
121.8 (d), 121.4 (d), 75.5 (s), 52.3 (t), 52.0 (q), 40.0 (t), 27.0 (t). IR
(neat) ν (cm-1) 2958, 2869, 1704, 1452, 1377. LRMS (m/z, rel
intensity) 231 (Mþ, 25), 202 (100), 172 (Mþ - C2H3O2, 15), 144
(40). HRMS calcd for C14H17N1O2 231.1259, found 231.1254.
Methyl (1S*,3R*,4S*)-3,4-Dihydroxyspiro[cyclopentane-1,10-iso-
indoline]-20-carboxylate (25). N-Mesylate 14c (0.141 g, 0.384 mmol)
was dissolved with dichloromethane (26 mL) and added into a
Rayonet reactor chamber equipped with 254 nm UV lamps.
Triethylamine (0.11 mL) was added to the reaction mixture and
the resulting solution was then exposed to UV light at -78 °C under
N2 atmosphere until no more starting material was seen by TLC
(4 h). Methanol (10 mL) was then added and the resulting solution
was allowed to stir for 15 h at room temperature. The solution was
then concentrated to yield an orange oil. The oil was then partitioned
between dichloromethane (50 mL) and H2O (25 mL). The aqueous
layer was extracted twice more with dichloromethane (25 mL). The
organic layers were combined, dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure to give an orange
oil. The oil was taken up in dichloromethane and purified by flash
chromatography on silica gel (1:2 to 6:1 EtOAc/hexanes) to yield 25
a clear oil (45 mg, 44%). Note that the 13C assignment contains both
rotamers. 1H NMR (300 MHz, CDCl3) δ(ppm) rotamer A: 7.79 (d,
1H, J = 7.3 Hz), 7.32 (t, 1H, J = 7.3 Hz), 7.24 (t, 1H, J = 7.3 Hz),
7.14 (d, 1H, J = 7.3 Hz), 4.75 (t, 2H, J = 4.4 Hz), 4.65 (s, 2H), 3.73
(s,3H), 2.89(brs, 2H), 2.68(dd, 2H,J= 14.6, 6.3 Hz), 2.18 (dd, 2H,
J = 14.6, 5.0 Hz); rotamer B: 7.79 (d, 1H, J = 7.7 Hz), 7.32 (t, 1H,
J = 7.7 Hz), 7.24 (t, 1H, J = 7.7 Hz), 7.14 (d, 1H, J = 7.7 Hz), 4.71
(s, 2H), 4.58-4.52 (m, 2H), 3.79 (s, 3H), 2,61 (dd, 2H, J = 14.9,
6.6 Hz), 2.20 (dd, 2H, J = 14.9, 5.0 Hz), 1.79 (br s, 2H). 13C NMR
(75.5 MHz, CDCl3) δ (ppm) rotamer A þ B: 154.6 (s), 147.8 (s),
133.7 (s), 128.4 (d), 127.3 (d), 123.8 (d), 121.3 (d), 74.7 (d), 73.2 (s),
Compound 23: 1H NMR (300 MHz, CDCl3) δ (ppm) rotamer
A: 5.10 (d, 1H, J = 4.7 Hz), 3.61 (s, 3H), 3.40-3.20 (m, 2H), 3.27
(s, 3H), 2.05-1.57 (m, 4H), rotamer B: 4.99 (d, 1H, J = 4.7 Hz),
3.61 (s, 3H), 3.40-3.20 (m, 2H), 3.20 (s, 3H), 2.05-1.57 (m, 4H).
13C NMR (75.5 MHz, CDCl3) δ (ppm) rotamer A: 156.3 (s),
89.0 (d), 55.7 (q), 52.3 (q), 45.6 (t), 31.8 (t), 22.6 (t); rotamer B:
156.3 (s), 88.4 (d), 55.0 (q), 52.3 (q), 45.8 (t), 32.3 (t), 21.6 (t).
LRMS (m/z, rel intensity) 144 (Mþ - CH3, 10), 128 (M- -OMe,
100). HRMS calcd for C6H10NO3 (Mþ - CH3) 144.0661, found
144.0663. IR (neat) ν (cm-1) 2951, 2886, 2839, 1700, 1446.
Compound 34: 1H NMR (300 MHz, CDCl3) δ (ppm) 4.78 (br s,
1H), 4.36 (t, 1H, J = 5.2 Hz), 3.65 (s, 3H), 3.32 (s, 6H), 3.19 (dd,
2H, J = 12.1, 6.1 Hz), 1.67-1.51 (m, 4H). 13C NMR (75.5 MHz,
CDCl3) δ (ppm) 157.0 (s), 104.2 (d), 52.9 (q), 52.0 (q), 40.7 (t),
29.7 (t), 25.0 (t). LRMS (m/z, rel intensity) 158 (Mþ - CH5O, 2),
144 (Mþ - C2H7O, 1), 128 (M - C2H7O2, 100). HRMS calcd for
C7H12NO3 (Mþ - C1H5O) 158.0817, found 158.0824. IR (neat) ν
(cm-1) 3342, 2949, 2830, 1708, 1540, 1258.
Methyl 2-Methoxypyrrolidine-1-carboxylate (23) and Methyl
4,4-Dimethoxybutylcarbamate (34) From 12c. N-Mesylate 12c
(0.261 g, 1.04 mmol) was dissolved with anhydrous methanol
(69 mL) and added into a Rayonet reactor chamber equipped
with 254 nm UV lamps. The reaction mixture was then exposed to
UV light at -78 °C under N2 atmosphere until completion (3 h). The
solution was then transferred to a round-bottomed flask containing
triethylamine (0.15 mL, 1.04 mmol) and left stirring for 30 min. The
solution was then concentrated under reduced pressure to a light
yellow oil. The oil was partitioned between dichloromethane (50 mL)
and H2O (50 mL). The aqueous was extracted twice more with
dichloromethane (25 mL). The organic layers were combined, dried
over anhydrous MgSO4, filtered, and concentrated under reduced
pressure to a yellow oil. The oil was taken up in dichloromethane and
purified by flash chromatography with a 1:1 to 9:1 ether/hexanes
solvent system to yield 23 as clear oil (0.108 g, 65%). The acetal 34
(50.1 mg, 30%) was also isolated as a colorless oil. See the formation
of the same compounds from 11c for the characterization data.
Methyl Spiro[cyclopentane-1,10-isoindoline]-20-carboxylate
(24). N-Mesylate 13c (0.201 g, 0.679 mmol) was dissolved with
dichloromethane (45 mL) and added into a Rayonet reactor
chamber equipped with 254 nm UV lamps. Triethylamine (0.19 mL,
1.36 mmol) was added to the reaction mixture and the resulting
solution was then exposed to UV light at -78 °C under N2 atmo-
sphere until no more starting material was seen by TLC (8 h).
Methanol (10 mL) was then added and the resulting solution was
allowed to stir for 15 h at room temperature. The solution was then
concentrated to yield a light yellow oil. The oil was then partitioned
between dichloromethane (50 mL) and H2O (25 mL). The aqueous
layer was extracted twice more with dichloromethane (25 mL). The
organic layers were combined, dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure to yield an orange
oil. The oil was taken up in dichloromethane and purified by flash
chromatography on silica gel (5:1 to 1:1 hexanes/diethyl ether) to
yield 24 as a clear oil (71 mg, 48%). 1H NMR (300 MHz, CDCl3)
δ (ppm) rotamer A: 7.31-7.16 (m, 4H), 4.73 (s, 2H), 3.79 (s, 3H),
2.62-2.38 (m, 2H), 2.22-2.12 (m, 2H), 2.09-1.78 (m, 4H); rotamer
B: 7.31-7.16 (m, 4H), 4.67 (s, 2H), 3.73 (s, 3H), 2.62-2.38 (m, 2H),
2.22-2.12 (m, 2H), 2.09-1.78 (m, 4H). 13C NMR (75.5 MHz,
CDCl3) δ (ppm) rotamer A: 154.2 (s), 149.5 (s), 133.8 (s), 128.0 (d),
127.0 (d), 121.8 (d), 121.4 (d), 75.5 (s), 53.1 (t), 52.0 (q), 41.3 (t), 27.0
(t); rotamer B: 154.2 (s), 149.5 (s), 133.8 (s), 128.0 (d), 127.0 (d),
53.1 (t), 52.3 (t), 52.3 (q), 47.6 (t), 46.4 (t). IR (neat) ν (cm-1
)
3560-3150 (br), 2949, 2869, 1681, 1452, 1381, 1112, 1085. LRMS
(m/z, rel intensity) 263 (Mþ, 20), 218 (40), 160 (100). HRMS calcd
for C14H17N1O4 263.1157, found 263.1164.
Photolysis Products 26 and 28. O-Mesylhydroxamic acid 15c
(400 mg, 1.62 mmol) was dissolved in methanol (110 mL) at
room temperature. The solution was transferred to a quartz cell,
cooled to -78 °C, and irradiated with 254 nm light in a Rayonet
for 3.5 h. The reaction mixture was transferred to a round-
bottomed flask and triethylamine (0.25 mL, 1.8 mmol) was
added. After being stirred at room temperature for 18 h, the
solvent was removed under reduced pressure. The residue was
dissolved in dichloromethane (25 mL) and water (25 mL). The
aqueous layer was extracted with dichloromethane (3 ꢀ 25 mL),
the organic extracts were then combined, dried over anhydrous
magnesium sulfate, filtered, and concentrated under reduced
pressure. The crude product was purified by flash chromatog-
raphy on silica gel, using ethyl acetate and hexanes (15:85 to
75:25) as eluent to give 26 as a colorless oil (139 mg, 47%) and 28
as a colorless oil (58 mg, 20%).
26: 1H NMR (300 MHz, CDCl3) δ (ppm) 3.67 (s, 3H), 3.65-
3.36 (m, 3H), 1.94-1.40 (m, 8H), 1.15 (s, 3H). 13C NMR (75.5
MHz, CDCl3) δ (ppm) rotamer A: 155.4 (s), 69.6 (d), 52.1 (q),
50.3 (s), 46.5 (t), 39.1 (t), 38.1 (t), 33.8 (t), 26.3 (q), 24.9 (t);
rotamer B: 155.4 (s), 69.0 (d), 52.1 (q), 49.4 (s), 46.1 (t), 39.1 (t),
37.5 (t), 32.9 (t), 26.3 (q), 24.9 (t). IR (neat) ν (cm-1) 2946, 2867,
1723, 1712, 1690, 1447, 1350, 1243, 1189, 1122, 1086. LRMS (m/z,
rel intensity) 183 (Mþ, 15), 168(60),140(100), 81(30). HRMScalcd
for C101H17NO2 183.1259, found 183.1254.
28: H NMR (300 MHz, CDCl3) δ (ppm) 5.28 (d, 1H, J =
3.8 Hz), 3.27 (s, 3H), 2.63-2.50 (m, 1H), 2.32 (ddd, 1H, J = 17.2,
9.8, 2.1 Hz), 2.05-1.33 (m, 8H), 1.37 (s, 3H). 13C NMR (75.5 MHz,
CDCl3) δ(ppm) 175.0(s),78.6(d),59.1(s),55.3(q),39.0(t),35.9(t),
29.9 (t), 29.3 (t), 24.4 (q), 15.7 (t). IR (neat) ν (cm-1) 2942, 2874,
2849, 2842, 1701, 1690, 1672, 1393, 1079. LRMS (m/z, rel intensity)
183 (Mþ, 5), 168 (100), 152 (100), 140(30), 98(50). HRMScalcdfor
C10H17NO2 183.1259, found 183.1254.
168 J. Org. Chem. Vol. 76, No. 1, 2011

Drouin et al.
JOCArticle
Photolysis Products 27 and 29. O-Mesylhydroxamic acid 16c
(230 mg, 0.879 mmol) was dissolved in methanol (60 mL) at
room temperature. The solution was transferred to a quartz cell,
cooled to -78 °C, and irradiated with 254 nm light in a Rayonet
for 2 h. The reaction mixture was transferred to a round-
bottomed flask and triethylamine (0.14 mL, 0.97 mmol) was
added. After the solution was stirred at room temperature for
18 h, the solvent was removed under reduced pressure. The
residue was dissolved in dichloromethane (25 mL) and water
(25 mL). The aqueous layer was extracted with dichloromethane
(2 ꢀ 25 mL), the organic extracts were then combined, dried over
anhydrous magnesium sulfate, filtered, and concentrated under
reduced pressure. The crude product was purified by flash
chromatography on silica gel with ethyl acetate and hexanes
(25:75 then 50:50) as eluent to give 27 as a colorless oil (94 mg,
54%) and 29 as a colorless oil (33 mg, 19%).
(100.7 MHz, CDCl3) δ (ppm) 175.1 (s), 139.5 (s), 131.4 (d), 129.4
(d), 128.4 (d), 71.9 (t), 56.0 (q), 30.7 (s), 16.4 (t). IR (neat, NaCl)
ν (cm-1) 3355, 2931, 2830, 1655, 1496, 1068. LRMS (m/z, rel
intensity) 205 (Mþ, 90), 173 (35), 117 (Mþ - C3H6NO2, 100).
HRMS calcd for C12H15NO2 205.1103, found 205.1102. Mp
68-72 °C.
Racemic Methyl anti-2,4-Dimethylpyrrolidine-1-carboxylate
(anti-36). The mesylhydroxamic acid anti-35c (112 mg, 0.507
mmol) was dissolved in methanol (35 mL), then the solution was
transferred to a quartz cell, cooled to -78 °C, and irradiated
with 254 nm light for 1 h. The reaction mixture was transferred
to a round-bottomed flask and triethylamine (80 μL, 0.55 mmol)
was added. After the solution was stirred at room temperature
for 15 min, the solvent was removed under reduced pressure.
The residue was dissolved in dichloromethane (25 mL) and
water (25 mL), the phases were separated, and the aqueous
layer was extracted with dichloromethane (2 ꢀ 25 mL). The
organic extracts were then combined, dried over anhydrous
magnesium sulfate, filtered, and concentrated. The crude prod-
uct was purified by flash chromatography with ethyl acetate
and hexanes (15:85) as eluent to give anti-36 as a colorless oil
27: 1H NMR (300 MHz, CDCl3) δ (ppm) 3.67 (s, 3H),
3.60-3.23 (m, 3H), 2.27-1.84 (m, 2H), 1.65-1.03 (m, 8H),
0.98 (s, 3H). 13C NMR (75.5 MHz, CDCl3) δ (ppm) rotamer A:
155.9 (s), 62.6 (d), 52.0 (q), 43.7 (t), 40.3 (s), 34.7 (t), 33.1 (t),
28.9 (t), 27.8 (q), 23.7 (t), 21.7 (t); rotamer B: 155.5 (s), 62.6 (d),
52.0 (q), 43.5 (t), 39.5 (s), 34.5 (t), 31.6 (t), 28.1 (t), 27.6 (q),
23.3 (t), 21.7 (t). IR (neat) ν (cm-1) 2958, 2936, 2861, 1704, 1452,
1386, 1107. LRMS (m/z, rel intensity) 197 (Mþ, 30), 182 ([M -
Me]þ, 100), 140 (80), 122 (30), 88 (30). HRMS calcd for
C11H19NO2 197.1416, found 197.1418.
1
(37 mg, 46%). H NMR (300 MHz, CDCl3) δ (ppm) mix of
rotamers: 4.07-3.80 (m, 2H), 3.65 (s, 6H), 3.60-3.42 (m, 2H),
2.97-2.75 (m, 2H), 2.43-2.24 (m, 2H), 1.71-1.51 (m, 4H), 1.17
(d, 3H, J=6.3 Hz), 1.12 (d, 3H, J=6.3 Hz), 1.00 (d, 6H, J=
6.4 Hz). 13CNMR(75.5MHz, CDCl3) δ(ppm) rotamer 1: 155.8 (s),
76.6 (q), 53.6 (t), 53.0 (d), 40.5 (t), 31.2 (d), 20.3 (q), 17.6 (q);
rotamer 2: 155.2 (s), 76.6 (q), 53.3 (t), 51.9 (d), 41.2 (t), 30.3 (d),
20.9 (q), 17.6 (q). IR (neat) ν (cm-1) 2964, 2937, 2817, 1701,
1450, 1379, 1188. LRMS (m/z, rel intensity) 157 (Mþ, 5), 142
([M - Me]þ, 100). HRMS calcd for C8H15NO2:157.1103, found
157.1107.
29: 1H NMR (300 MHz, CDCl3) δ (ppm) 5.37 (dd, 1H, J1 =
8.2 Hz and J2 = 6.0 Hz), 3.21 (s, 3H), 2.40 (dd, 2H, J1 = 8.8 Hz
and J2 = 7.2 Hz), 2.06-1.92 (m, 1H), 1.85-1.49 (m, 8H), 1.34
(s, 3H), 1.27-1.12 (m, 1H). 13C NMR (75.5 MHz, CDCl3) δ(ppm)
176.1 (s), 83.0 (d), 63.9 (s), 55.8 (q), 39.5 (t), 34.9 (t), 33.7 (t), 29.8
(t), 25.8 (q), 25.0 (t), 22.7 (t). IR (neat) ν (cm-1) 2936, 2861, 1695,
1461, 1403, 1337, 1081. LRMS (m/z, rel intensity) 197 (Mþ, 1),
182 ([M - Me]þ, 50), 166 (40), 98 (100). HRMS calcd for
Racemic Methyl syn-2,4-Dimethylpyrrolidine-1-carboxylate
(syn-36). The mesylhydroxamic acid syn-35c (142 mg, 0.64
mmol) was dissolved in methanol (42 mL). The solution was
transferred to a quartz cell, cooled to -78 °C, and irradiated
with 254 nm light for 1 h. The reaction mixture was transferred
to a round-bottomed flask and triethylamine (0.10 mL, 0.70 mmol)
was added. After the solution was stirred at room temperature
for 15 min, the solvent was removed under reduced pressure.
The residue was dissolved in dichloromethane (25 mL) and
water (25 mL), the phases were separated ,and the aqueous
layer was extracted with dichloromethane (2 ꢀ 25 mL). The
organic extracts were combined, dried over anhydrous magne-
sium sulfate, filtered, and concentrated. The crude product was
purified by flash chromatography with ethyl acetate and hex-
anes (15:85) as eluent to give syn-36 as a colorless oil (58 mg,
C
11H19NO2 197.1416, found 197.1412. Mp 40-44 °C.
N-Methyl O-Methyl 1-Phenylcyclopropylcarbamate (31) and
N-(Methoxymethyl)-1-phenylcyclopropanecarboxamide (32).
N-Mesylate 30c (0.120 g, 0.447 mmol) was dissolved in methanol
(30 mL) and added to a Rayonet reactor chamber equipped with
254 nm UV lamps. The reaction mixture was then exposed to
UV light at -78 °C under N2 atmosphere until no more starting
material was seen by TLC (6 h). The solution was then con-
centrated to a light yellow oil. The oil was dissolved with
dichloromethane (30 mL) and washed with H2O (30 mL). The
aqueous layer was extracted twice more with dichloromethane
(30 mL). The organic layers were then combined, dried over
MgSO4, filtered, and concentrated under reduced pressure to a
yellow oil. The oil was taken up in dichloromethane and purified
by flash chromatography on silica gel (6:1 hexanes/diethyl ether
to 100% diethyl ether to 1:1 MeOH: EtOAc) to yield 31 as a clear
oil (16 mg, 18%) and 32 as a white solid (60 mg, 60%). Note that
characterization includes both rotamers.
1
58%). H NMR (300 MHz, CDCl3) δ (ppm) mix of rotamers:
3.90-3.76 (m, 2H), 3.65 (s, 3H), 2.85-2.68 (dd, 1H, J=10.2,
10.2 Hz), 2.28-2.14 (m, 1H), 2.13-1.94 (m, 1H), 1.33-1.15
(m, 3H), 1.14-1.03 (m, 1H), 0.99 (d, 3H, J=6.5 Hz). 13C NMR
(75.5 MHz, CDCl3) δ (ppm) rotamer 1: 155.8 (s), 54.2 (q),
53.6 (t), 51.9 (d), 42.6 (t), 32.5 (d), 20.6 (q), 17.1 (q); rotamer
2: 155.3 (s), 54.2 (q), 53.8 (t), 51.9 (d), 43.3 (t), 32.3 (d), 21.6 (q),
17.1 (q). IR (neat) ν (cm-1) 2960, 2930, 2874, 1705, 1450, 1383,
1203, 1106, 769. LRMS (m/z, rel intensity) 157 (Mþ, 10), 142
([M - Me]þ, 100). HRMS calcd for C8H15NO2 157.1103, found
157.1099.
31: 1H NMR (300 MHz, CDCl3) δ (ppm) 7.33-7.28 (m, 2H),
7.22-7.18 (m, 2H), 7.06-7.03 (m, 1H), 3.70 (s, 3H), 3.01 (s, 3H),
2.96 (s, 3H), 1.38-1.21 (m, 8H). 13C NMR (75.5 MHz, CDCl3)
δ (ppm) 158.2 (s), 142.1 (s), 141.3 (s), 128.4 (d), 126.4(d),
126.1 (d), 125.7 (d), 124.6 (d), 52.7 (q), 52.4 (q), 41.9 (s), 34.7
(q), 34.5 (s), 29.7 (t), 20.4 (t), 18.8 (t). IR (neat, NaCl) ν (cm-1
)
2958, 2922, 2852, 1708, 1456, 1368, 1200, 1160. LRMS (m/z, rel
intensity) 205 (Mþ, 65), 204 (60), 147 (50), 118 (100), 91 (50).
HRMS calcd for C12H15NO2 205.1103, found 205.1104.
32: 1H NMR (400 MHz, CDCl3) δ (ppm) 7.43-7.30 (m, 5H),
6.00 (br s, 1H), 4.57 (d, 2H, J = 6.9 Hz), 3.26 (s, 3H), 1.65-
1.63 (AB quartet, 2H), 1.12-1.09 (AB quartet, 2H). 13C NMR
Supporting Information Available: Procedures and charac-
terization data for all new compounds and X-ray crystallo-
graphic data for 76a. This material is available free of charge via
the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 76, No. 1, 2011 169